The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes1,2. Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia3. Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle4 and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor affinity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions.
- MeSH
- glukosa * metabolismus MeSH
- glukosidy aplikace a dávkování chemie farmakologie terapeutické užití MeSH
- hypoglykemie * farmakoterapie metabolismus chemicky indukované MeSH
- inzulin * aplikace a dávkování analogy a deriváty metabolismus farmakologie terapeutické užití MeSH
- krevní glukóza * metabolismus MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- makrocyklické sloučeniny aplikace a dávkování chemie farmakologie terapeutické užití MeSH
- potkani Sprague-Dawley MeSH
- prasata MeSH
- receptor inzulinu metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glukosa * MeSH
- glukosidy MeSH
- inzulin * MeSH
- krevní glukóza * MeSH
- makrocyklické sloučeniny MeSH
- receptor inzulinu MeSH
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
- MeSH
- benzhydrylové sloučeniny aplikace a dávkování škodlivé účinky MeSH
- chronická nemoc MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- glifloziny aplikace a dávkování škodlivé účinky MeSH
- glukosidy aplikace a dávkování škodlivé účinky MeSH
- hospitalizace statistika a číselné údaje MeSH
- kardiovaskulární nemoci mortalita prevence a kontrola MeSH
- lidé MeSH
- srdeční selhání farmakoterapie patofyziologie MeSH
- tepový objem * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- benzhydrylové sloučeniny MeSH
- empagliflozin MeSH Prohlížeč
- glifloziny MeSH
- glukosidy MeSH
(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.
- Klíčová slova
- cell senescence, empagliflozin, hereditary hypertriglyceridemic rat model, hypertriglyceridemia, insulin sensitivity, metabolic syndrome,
- MeSH
- aplikace orální MeSH
- benzhydrylové sloučeniny aplikace a dávkování MeSH
- buňky 3T3-L1 MeSH
- buňky Hep G2 MeSH
- down regulace účinky léků MeSH
- dyslipidemie farmakoterapie MeSH
- glifloziny aplikace a dávkování MeSH
- glukoneogeneze účinky léků genetika MeSH
- glukosidy aplikace a dávkování MeSH
- hmotnostní přírůstek účinky léků MeSH
- hypertriglyceridemie farmakoterapie metabolismus MeSH
- hypoglykemika aplikace a dávkování MeSH
- inzulinová rezistence MeSH
- játra metabolismus MeSH
- krysa rodu Rattus MeSH
- ledviny metabolismus MeSH
- lidé MeSH
- lipogeneze účinky léků genetika MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- oxidační stres účinky léků MeSH
- stárnutí buněk účinky léků MeSH
- tuková tkáň metabolismus MeSH
- upregulace účinky léků MeSH
- viabilita buněk účinky léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzhydrylové sloučeniny MeSH
- empagliflozin MeSH Prohlížeč
- glifloziny MeSH
- glukosidy MeSH
- hypoglykemika MeSH
BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
- Klíčová slova
- diuretics, heart failure, sodium-glucose transporter 2 inhibitors,
- MeSH
- benzhydrylové sloučeniny aplikace a dávkování MeSH
- diuretika aplikace a dávkování MeSH
- glukosidy aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční selhání farmakoterapie patofyziologie MeSH
- tepový objem účinky léků MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- benzhydrylové sloučeniny MeSH
- dapagliflozin MeSH Prohlížeč
- diuretika MeSH
- glukosidy MeSH
In solid tumors, hypoxia (lack of oxygen) is developed, which leads to the development of resistance of tumor cells to chemotherapy and radiotherapy through various mechanisms. Nevertheless, hypoxic cells are particularly vulnerable when glycolysis is inhibited. For this reason, in this study, the development of magnetically targetable nanocarriers of the sodium-glucose transporter protein (SGLT2) inhibitor dapagliflozin (DAPA) was developed for the selective delivery of DAPA in tumors. This nanomedicine in combination with radiotherapy or chemotherapy should be useful for effective treatment of hypoxic tumors. The magnetic nanoparticles consisted of a magnetic iron oxide core and a poly(methacrylic acid)-graft-poly(ethyleneglycol methacrylate) (PMAA-g-PEGMA) polymeric shell. The drug (dapagliflozin) molecules were conjugated on the surface of these nanoparticles via in vivo hydrolysable ester bonds. The nanoparticles had an average size of ~ 70 nm and exhibited a DAPA loading capacity 10.75% (w/w) for a theoretical loading 21.68% (w/w). The magnetic responsiveness of the nanoparticles was confirmed with magnetophoresis experiments. The dapagliflozin-loaded magnetic nanoparticles exhibited excellent colloidal stability in aqueous and biological media. Minimal (less than 15% in 24 h) drug release from the nanoparticles occurred in physiological pH 7.4; however, drug release was significantly accelerated in pH 5.5. Drug release was also accelerated (triggered) under the influence of an alternating magnetic field. The DAPA-loaded nanoparticles exhibited higher in vitro anticancer activity (cytotoxicity) against A549 human lung cancer cells than free DAPA. The application of an external magnetic field gradient increased the uptake of nanoparticles by cells, leading to increased cytotoxicity. The results justify further in vivo studies of the suitability of DAPA-loaded magnetic nanoparticles for the treatment of hypoxic tumors.
- Klíčová slova
- cytotoxicity, dapagliflozin, drug targeting, hypoxia, magnetic nanoparticles, tumor,
- MeSH
- benzhydrylové sloučeniny aplikace a dávkování chemie MeSH
- buňky A549 MeSH
- glifloziny MeSH
- glukosidy aplikace a dávkování chemie MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- magnetické nanočástice aplikace a dávkování chemie MeSH
- nádorová hypoxie účinky léků fyziologie MeSH
- nádorové buněčné linie MeSH
- nanomedicína metody MeSH
- nosiče léků aplikace a dávkování chemie MeSH
- transportér 2 pro sodík a glukózu MeSH
- uvolňování léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzhydrylové sloučeniny MeSH
- dapagliflozin MeSH Prohlížeč
- glifloziny MeSH
- glukosidy MeSH
- magnetické nanočástice MeSH
- nosiče léků MeSH
- SLC5A2 protein, human MeSH Prohlížeč
- transportér 2 pro sodík a glukózu MeSH
Fixed dose combination of two different drugs in the same or related indications are successfully used in various medical fields including diabetology. This article deals with the combination therapy comprising metformin and dapagliflozin in a single preparation, molecules affecting different pathophysiological mechanisms of type 2 diabetes, particularly insulin resistance and increased glucose reabsorption in the kidney. Most patients with type 2 diabetes does not achieve target glycemic control when treated with single antidiabetics and need for proper control of diabetes combination of several different drugs. Using the fixed combination leads to improved patients adherence and utilization of the full therapeutic potential of selected drugs.
- MeSH
- benzhydrylové sloučeniny aplikace a dávkování MeSH
- diabetes mellitus 2. typu farmakoterapie MeSH
- fixní kombinace léků MeSH
- glukosidy aplikace a dávkování MeSH
- hypoglykemika aplikace a dávkování MeSH
- lidé MeSH
- metformin aplikace a dávkování MeSH
- transportní proteiny pro sodík a glukosu antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzhydrylové sloučeniny MeSH
- dapagliflozin MeSH Prohlížeč
- fixní kombinace léků MeSH
- glukosidy MeSH
- hypoglykemika MeSH
- metformin MeSH
- transportní proteiny pro sodík a glukosu MeSH
Gastrodin, a main constituent of a Chinese herbal medicine, has been shown to be effective in treating various mood disorders. The purpose of the present study was to determine whether gastrodin could ameliorate stress-associated behavior in a rat model of enhanced single prolonged stress (ESPS)-induced posttraumatic stress disorder (PTSD). Following ESPS, rats were administered orally with gastrodin (50, 100, or 200 mg/kg daily) or vehicle for 2 weeks. Animals were then tested in the open field and elevated plus-maze, and the levels of IL-6 and IL-1beta, the expression of iNOS, p38 and phospho-p38 (p-p38) in hippocampus were also tested. ESPS exposure resulted in pronounced anxiety-like behavior, elevated IL-6 and IL-1beta levels, and the higher expression of iNOS and p-p38 in hippocampus. However, repeated treatment with gastrodin, particularly at higher doses, reversed the aforementioned changes, including anxiety-like behavior, levels of IL-6 and IL-1beta, and the expression of iNOS and the p38 MAPK phosphorylation. These results indicate that gastrodin possesses anxiolytic effect and may be an effective herbal preparation for the treatment of PTSD.
- MeSH
- anxiolytika aplikace a dávkování farmakologie MeSH
- aplikace orální MeSH
- benzylalkoholy aplikace a dávkování farmakologie MeSH
- časové faktory MeSH
- chování zvířat účinky léků MeSH
- fosforylace MeSH
- glukosidy aplikace a dávkování farmakologie MeSH
- hipokampus účinky léků enzymologie MeSH
- interleukin-1beta metabolismus MeSH
- interleukin-6 metabolismus MeSH
- krysa rodu Rattus MeSH
- léky rostlinné čínské aplikace a dávkování farmakologie MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- modely nemocí na zvířatech MeSH
- pohybová aktivita účinky léků MeSH
- posttraumatická stresová porucha farmakoterapie enzymologie psychologie MeSH
- potkani Sprague-Dawley MeSH
- synthasa oxidu dusnatého, typ II metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- anxiolytika MeSH
- benzylalkoholy MeSH
- gastrodin MeSH Prohlížeč
- glukosidy MeSH
- interleukin-1beta MeSH
- interleukin-6 MeSH
- léky rostlinné čínské MeSH
- mitogenem aktivované proteinkinasy p38 MeSH
- Nos2 protein, rat MeSH Prohlížeč
- synthasa oxidu dusnatého, typ II MeSH
